Batten disease, a childhood neurodegenerative disorder results from mutations in CLN3. Patients with Batten disease and a cln3-knockout mouse have autoantibodies to several proteins including GAD65. Moreover, these autoantibodies have been shown to associate to the brain in post-mortem Batten disease tissue and in the brain of cln3-knockout mice. In the previous cycle of this grant we had proposed to establish that the autoimmune component contributed to the pathogenesis of Batten disease. In the progress report we detail publications and preliminary data that confirm a neuroimmune component to the pathogenesis of Batten disease. In addition, completion of the main aim of the original proposal, namely construction of cln3 knockout mice that are also homozygous for deletion of MuMT (the immunoglobulin mu chain) or C-alpha-mice (the alpha chain of the T-cell receptor) so they therefore lack the ability to generate B-cells, and CD4+ and CD8+ T- cells, respectively, confirms an amelioration of deteriorating motor coordination resulting from mutation of CLN3. The goal of this competitive renewal is to more specifically identify the components of the autoimmune response that contribute to the pathogenesis of Batten disease. Having established that genetic suppression of the immune system slows disease progression, we will establish whether drug mediated immune suppression using a drug that is tolerable to children can slow progression of disease. Finally, we present published and preliminary data that the novel anti-GAD65 response forms a part of a wider autoimmune response. We will therefore identify the multiple autoantigens in Batten disease to gain a greater understanding of how the autoimmune response imparts its effect on neuronal function and to develop further targets for treatment strategies. We shall (i) define the inflammatory response to the presence of autoantibodies and the participation of the innate immune system in the disease process in cln3-knockout mice by examining cytokines such as IL-1 and TNF-a, complement proteins and microglial activation, respectively. (ii) We will treat cln3-knockout and control mice with immunosuppressant Mycophenolate Mofetil (CellCept) that is suitable for children, and could provide the foundation for a treatment for Batten disease. Finally we will identify additional autoantigens in batten disease by proteomic approaches. This work may lead to treatment strategies for the fatal disorder, Batten disease. Moreover, the described approach may be applied to other rare genetically inherited disorders. PUBLIC HEALTH RELEVANCE: The proposed research is relevant and significant as it has the potential to increase our understanding of Batten's Disease and ultimately impact therapeutic strategies for this disease.